Clinical trials are research studies carried out in human participants to evaluate medical interventions. Clinical trials are conducted when there is significant evidence suggesting a new treatment will improve the care of patients with a particular disease. Before a clinical trial is conducted, tests and experiments are conducted to assess the treatment. This is called preclinical research. This research is not performed in humans. All drugs go through preclinical research to gain insight before human trials. Preclinical research often involves animals. After preclinical research shows that a treatment is relatively safe and shows evidence it may be effective, clinical trials are conducted. Clinical trials are used to ensure the treatment works and is safe for human use. Trials are broken down into phases allowing different information to be attained (1). Phase 1: Phase 1 aims to determine the optimal dose of a medicine with the least amount of side effects. At this stage, the trial group is small (15-30 patients). Low doses of a medication are given and slowly increased throughout the trial until the side effects become intolerable or the desired outcome is observed. The goal of Phase 1 is to assess the safety and tolerability of a drug. It is not yet known if the drug will be effective or not. Once the drug is demonstrated to be reasonably safe for a short period of time, it moves on to Phase 2.
Phase 2: Phase 2 trials continue to assess the safety of a drug while starting to focus on measuring the effectiveness. The trial group in this phase is a bit larger. Once the drug has shown that it works in this preliminary group and continues to be reasonably safe, it moves on to Phase 3.
Phase 3: Majority of drugs that will fail, fail in this phase (2). Phase 3 aims to compare the new medication to the standard of care treatment (if available) and are conducted in a large population of 100 or more participants. These studies compare the side effects and whether the new medication is as effective as prior ones. If there is no standard available treatment, a placebo (sugar pill) may be used. Patients participating are randomly put into treatment groups and given either the standard of care if available, placebo, or the new drug of interest. Neither the doctors or the patients know what group they are assigned to reduce any bias from the doctor, providers, or how the patient reports symptoms.
Since TGCT has no current standard of care, Phase 3 trials are often done with a placebo group. This means that patients are either given the drug of interest or a sugar pill. Neither the doctors nor the patients know what the patient receives. Oftentimes, patients in the placebo group are allowed to switch into the treatment group or the identity of the groups is revealed after a certain amount of time has gone by, this is called a crossover design. At any phase, the trial will be stopped if side effects become too severe. In order for the FDA to approve a treatment for the general public, Phase 3 trials are required and are known as "pivotal" trials.
Oftentimes, Phase 3 trials include a placebo group to ensure the effectiveness of the drug of interest does not occur because of other factors or chance. For many TGCT Phase 3 trials, patients have higher chances of receiving the drug of interest than the placebo. For example, for every 3 TGCT patients that enter a Phase 3 trial, 2 may receive the drug of interest and 1 may receive the placebo. This allows more patients to receive the drug-of-interest faster while the 1 patient that received the placebo will be offered the drug of interest later in the trial. During any of the phases, blinding and randomization are considered the gold standard design components for trials. Blinding refers to the patient and provider not knowing who receives what treatment. This reduces bias between the doctors, providers, and patients. However, if there is a severe side effect reported, patients can be unblinded to ensure safety. Randomization means that patients are assigned to a treatment based off random chance and not based on timeliness of enrolling into the trial, severity of disease, patient or provider preference. This allows demographic features to be comparable between treatment groups.
For TGCT, due to it being an orphan disease with no medicine options until Pexidartinib was approved in 2019, there are ongoing trials to improve the tolerability and effectiveness of these CSF1 inhibitors.
Current Clinical Trials for TGCT
DCC-3014, Vimseltinib (Deciphera) is the name of a medication currently in development for TGCT. It was previously tested in a Phase 3 study, meaning the long-term side effects are being evaluated as well as the effectiveness of the drug over the course of 52 weeks. The Phase 3 trial was known as MOTION. Data shows it has an improved tolerability profile and remains effective at shrinking the tumor. It has ended its recruitment at 18 different global clinical locations and has submitted a marketing application for approval in the United States. The approval decision is expected February 17, 2025. For more information on the trial and the locations, visit the Phase 2 clinical trial website for DCC-3014, Phase 3 clinical trial website for Vimseltinib or ask your healthcare provider. To learn more, check out Deciphera's Vimseltinib page.
AMB-05X (AmMax Bio, Inc.) is a monoclonal antibodies that targets CSF1R intended to be injected directly into the affected joint. Monoclonal antibodies are laboratory made protein that target a specific protein, like CSF1. While both Vimseltinib and Pexidartinib are small molecule-based drugs (like many oral pills available), this drug relies on a protein antibody that blocks CSF1 by holding onto it and preventing it from reaching TGCT and surrounding cells. This trial was intended to evaluate the effectiveness safety, toxicity, and tolerability of AMB-05X as a 12 week treatment. This trial has halted recruitment and the status of future development is unknown. For more information, visit the clinical trial website for AMB-05X or ask your healthcare provider.
Pimicotinib (ABSK021) is a daily oral investigational drug that is currently investigated in a Phase 3 clinical trial for the treatment of TGCT. This trial intended to evaluate the effectiveness and long-term safety of the treatment taken daily for a total of 24 weeks. Patients received a placebo or the drug being investigated. Neither patients nor their providers know who received the drug or placebo for 24 weeks. After 24 weeks, patients will be notified whether they received the placebo or the drug and patients that received the placebo will be allowed to receive the drug for 24 additional weeks. Patients who received the drug in the first 24 weeks will continue to receive it if they are benefitting from it. This trial has completed enrollment and results have not been published yet. For more information on the trial, visit the Phase 3 clinical trial or ask your healthcare provider.
Emactuzumab (SynOx Therapeutics) is a monoclonal antibody that is designed to target CSF1 and block it from signaling to TGCT and surrounding cells. Monoclonal antibodies are laboratory made protein that target a specific protein, like CSF1. A Phase 3 randomized study is being recruited currently, meaning the optimal dose is known and the effectiveness is being investigated. Emactuzumab is administered every 2 weeks by infusion for a 10-week treatment period (5 infusions total). Patients will be randomized to receive either a placebo or emactuzumab for the treatment period. Patients receiving placebo will have the option to receive emactuzumab following the initial treatment period. The Phase 3 trial is known as TANGENT. It has started recruiting, starting at MedStar in DC and Sarcoma Oncology Research Center in California. Clinical trial sites in Belgium (Brussels), Italy (Bologna, Pisa, and Sicily), Netherlands (LUMC), Spain (Barcelona and Zaragoza), Taiwan (Taipei), Sweden (Lund), Switzerland (Basel), France (Lyon and other sites), Montreal and Toronto (Canada), and the UK (London) are open. For more information and updates on the ongoing status, visit the clinical trial website for Emactuzumab, check back here, or ask your healthcare provider.
Cabiralizumab (FPA008, Five Prime Therapeutics) completed Phase 1/2 trials to evaluate the safety, tolerability, and effectiveness of Cabiralizumab in diffuse TGCT. This clinical trial took place at 12 different global clinical locations. For more information, visit the clinical trial website for Cabiralizumab or ask your healthcare provider. As of 2021, Amgen has acquired this company. It is unknown whether this drug will continue.
Lastly, trials are in place to evaluate discontinuation and re-treatment with the currently approved Turalio (Pexidartinib). These trials are in place to set a guideline for treatment duration and discontinuation post FDA-approval. This trial is being conducted at 15 different global clinical sites. For more information, visit the clinical trial website for Turalio or ask your healthcare provider.
References
1. Phases of clinical trials. NCCN Guidelines for Patients. https://www.nccn.org/patients/resources/clinical_trials/phases.aspx. Published 2021. 2. Fogel DB. Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: A review. Contemp Clin Trials Commun. 2018. doi:10.1016/j.conctc.2018.08.001
